A Phase 3 Clinical Trial to Evaluate the Safety and Efficacy of Ensifentrine in Patients With COPD
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|ClinicalTrials.gov Identifier: NCT04535986|
Recruitment Status : Active, not recruiting
First Posted : September 2, 2020
Last Update Posted : December 6, 2022
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|Condition or disease||Intervention/treatment||Phase|
|Chronic Obstructive Pulmonary Disease||Drug: Ensifentrine Drug: Placebo||Phase 3|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||800 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Double (Participant, Investigator)|
|Official Title:||A Phase III Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Ensifentrine Over 24 Weeks (With a 48-week Safety Subset) in Subjects With Moderate to Severe COPD|
|Actual Study Start Date :||September 29, 2020|
|Actual Primary Completion Date :||September 12, 2022|
|Estimated Study Completion Date :||November 28, 2022|
Experimental: Arm 1
Ensifentrine Nebulized Suspension; 3 mg BID
• Dosage Formulation: Ensifentrine Nebulizer suspension
Placebo Comparator: Arm 2
Placebo Nebulized BID
• Dosage Formulation: Ensifentrine Nebulizer suspension
- Average forced expiratory volume in 1 second (FEV1) area under the curve (AUC)0-12h [ Time Frame: 12 weeks ]Change from baseline of Average forced expiratory volume in 1 second (FEV1) area under the curve (AUC)0-12h
- Average FEV1 AUC0-4h post-dose at Week 12 [ Time Frame: 12 weeks ]Change from baseline of Average FEV1 AUC0-4h post-dose at Week 12
- Peak FEV1 over 4 hours post dose at Week 12 [ Time Frame: 12 weeks ]Change from baseline in Peak FEV1 over 4 hours post dose at Week 12
- Weekly average of Evaluating-Respiratory Symptoms (E-RS) Total Score at Week 24 [ Time Frame: 24 weeks ]Change from baseline as a weekly average of Evaluating-Respiratory Symptoms (E-RS) Total Score at Week 24
- St. George's Respiratory Questionnaire (SGRQ) total score at Week 24 [ Time Frame: 24 weeks ]Change from baseline of SGRQ total score at Week 24
- Morning trough FEV1 at Week 12 [ Time Frame: 12 weeks ]Change from baseline of Morning trough FEV1 at Week 12
- St. George's Respiratory Questionnaire (SGRQ) [ Time Frame: 24 weeks ]The proportion of St. George's Respiratory Questionnaire (SGRQ) responders at Week 24.
- Rescue medication use at Week 24 [ Time Frame: 24 weeks ]Change from baseline of Rescue medication use at Week 24
- Transitional Dyspnea Index (TDI) at Week 24 [ Time Frame: 24 weeks ]Transitional Dyspnea Index (TDI) at Week 24
- Evening trough FEV1 at Week 12 [ Time Frame: 12 weeks ]Change from baseline Evening trough FEV1 at Week 12
- Peak FEV1 at Week 6 and Week 24 [ Time Frame: 6 and 24 weeks ]Change from baseline Peak FEV1
- Morning trough FEV1 at Week 6 and Week 24 [ Time Frame: 6 and 24 weeks ]Change from baseline morning trough FEV1
- Evening trough FEV1 at Week 6 and Week 24 [ Time Frame: 6 and 24 weeks ]Change from baseline evening trough FEV1
- FEV1 AUC0-4h at Week 6 and Week 24 [ Time Frame: 6 and 24 weeks ]Change from baseline FEV1 AUC0-4h
- Evaluating-Respiratory Symptoms (E-RS) Total Score at Week 6 and Week 12 [ Time Frame: 6 and 12 weeks ]Change from baseline E-RS Total Score
- St. George's Respiratory Questionnaire (SGRQ) responder analysis at Week 6 and Week 12 [ Time Frame: 6 and 12 weeks ]Change from baseline SGRQ responder analysis
- TDI at Week 6 and Week 12 [ Time Frame: 6 and 12 Weeks ]Change from baseline TDI
- St. George's Respiratory Questionnaire (SGRQ) total score at Weeks 6 and 12 [ Time Frame: 6 Weeks and 12 weeks ]Change from baseline of SGRQ total score at Weeks 6 and 12
- Rescue medication use at Weeks 6 and 12 [ Time Frame: 12 weeks ]Change from baseline of Rescue medication use at Weeks 6 and 12
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|Ages Eligible for Study:||40 Years to 80 Years (Adult, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
Capable of giving informed consent indicating that they understand the purpose of the study and study procedures and agree to comply with the requirements and restrictions listed in the informed consent form (ICF).
Age and Sex
- Age: Patient must be 40 to 80 years of age inclusive, at the time of Screening.
- Males are eligible to participate if they agree to use contraception as described in the contraceptive guidance from Screening and throughout the study and for at least 30 days after the last dose of blinded study medication.
Females are eligible to participate if they are not pregnant, not breastfeeding, and at least one of the following conditions apply:
- Not a woman of childbearing potential (WOCBP) as defined in Or
- A WOCBP who agrees to follow the contraceptive guidance from Screening and throughout the study and for at least 30 days after the last dose of blinded study medication.
Smoking History: Current or former cigarette smokers with a history of cigarette smoking ≥10 pack years at Screening (Visit 0) [number of pack years = (number of cigarettes per day / 20) × number of years smoked (eg, 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years)]. Pipe and/or cigar use cannot be used to calculate pack-year history. Former smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 0. Smoking cessation programs are permitted during the study.
COPD Diagnosis, Symptoms, Severity and Maintenance Therapy
- COPD Diagnosis: Patients with an established clinical history of COPD as defined by the American Thoracic Society (ATS)/European Respiratory Society (ERS) guidelines with symptoms compatible with COPD.
- COPD Symptoms: A score of ≥2 on the Modified Medical Research Council (mMRC) Dyspnea Scale.
- Pre- and Post-albuterol/salbutamol FEV1/FVC ratio of <0.70.
- Post-albuterol/salbutamol FEV1 ≥30 % and ≤70% of predicted normal calculated using the National Health and Nutrition Examination Survey III.
Maintenance Therapy: Patients on no maintenance/background therapy or patients on stable maintenance LAMA or LABA therapy are eligible. Patients taking maintenance LAMA or LABA therapy must demonstrate stable use of the maintenance LAMA or LABA therapy for at least 3 months prior to Screening and agree to continue use for the duration of the study. Background maintenance LAMA or LABA bronchodilator therapy will be capped at 50% of patients.
Other Requirements for Inclusion
- Capable of withholding SABAs for 4 hours prior to initiation of any spirometry. Patients in the maintenance LAMA or LABA therapy stratum must be capable of withholding Twice-Daily maintenance LAMA or LABA for 24 hours and Once-Daily maintenance LAMA or LABA for 48 hours prior to initiation of any spirometry.
- Capable of using the study nebulizer correctly and complying with all study restrictions and procedures.
- Ability to perform acceptable spirometry in accordance with ATS/ERS guidelines.
Inclusion Criteria at Randomization (RPL554-CO-301)
- Symptoms of COPD: A score of ≥2 on the mMRC Dyspnea Scale.
- Completion of the e-Diary at least 5 of the last 7 days of the Run-in period.
Current Condition or Medical History
- History of life-threatening COPD including Intensive Care Unit admission and/or requiring intubation.
- Hospitalizations for COPD, pneumonia, or Corona Virus Disease 2019 (COVID-19) in the 12 weeks prior to Screening and/or a positive COVID-19 test result indicating an active infection at Screening. Patients with COVID-19 antibodies from a previous exposure with no active infection are not excluded.
- COPD exacerbation requiring oral or parenteral steroids within 3 months of Screening.
- Previous lung resection or lung reduction surgery within 1-year of Screening.
- Long term oxygen use defined as oxygen therapy prescribed for greater than 12 hours per day. As needed oxygen use (≤12 hours per day) is not exclusionary.
- Pulmonary rehabilitation, unless such treatment has been in a stable maintenance phase for 4 weeks prior to Visit 1 and remains stable during the study.
- Lower respiratory tract infection within 6 weeks of Screening.
- Other respiratory disorders including, but not limited to, a current diagnosis of asthma, active tuberculosis, lung cancer, sarcoidosis, lung fibrosis, interstitial lung diseases, unstable sleep apnea, known alpha-1 antitrypsin deficiency, core pulmonale, clinically significant pulmonary hypertension, clinically significant bronchiectasis, or other active pulmonary diseases.
- Major surgery (requiring general anesthesia) in the 6 weeks prior to Screening, lack of full recovery from surgery at Screening, or planned surgery through the end of the study.
Historical or current evidence of clinically significant cardiovascular disease defined as any disease that in the opinion of the Investigator would put the safety of the patient at risk through participation or which could affect the efficacy or safety analysis if the disease/condition were to exacerbate during the study, including, but not limited to:
- Myocardial infarction or unstable angina within 6 months prior to Screening.
- Unstable or life-threatening cardiac arrhythmia requiring intervention within 3 months prior to Screening.
- Diagnosis of New York Heart Association Class III and Class IV heart failure.
- Chronic uncontrolled disease including, but not limited to, endocrine, active hyperthyroidism, neurological, hepatic, gastrointestinal, renal, hematological, urological, immunological, psychiatric, or ophthalmic diseases that the Investigator believes are clinically significant.
- Unstable liver disease defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices or persistent jaundice, cirrhosis, known biliary abnormalities (except for Gilbert's syndrome or asymptomatic gallstones).
- History of or current malignancy of any organ system, treated or untreated within the past 5 years, except for localized basal or squamous cell carcinoma of the skin.
Findings on physical examination that an investigator considers to be clinically significant at Screening.
Use of prohibited medications within the time intervals.
History or Suspicion of Drug or Alcohol Abuse
Current or history of past drug or alcohol abuse within the past 5 years.
Laboratory and Other Diagnostic Parameters
- Glomerular Filtration Rate (eGFR) <30 mL/min. The Chronic Kidney Disease Epidemiology Collaboration Creatinine (2009) calculation will be used (Levey, 2009).
- Alanine aminotransferase (ALT) ≥ 2 x upper limit of normal (ULN), alkaline phosphatase and/or bilirubin > 1.5 x ULN (isolated bilirubin >1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
Hepatitis B antibody:
- Positive findings for both Hepatitis B surface antigen (HBsAg) and Hepatitis B core antibody (anti-HBc) are excluded, as this indicates acute or chronic infection.
- Negative findings for HBsAg and Hepatitis B surface antibody (anti-HBs) but positive findings for anti-HBc are excluded as this may indicate current or resolving infection.
- Positive findings for anti-HBc and anti-HBs but negative findings for HBsAg are not excluded, as this indicates immunity due to natural infection.
- Positive findings for anti-HBs but negative findings for HBsAg and anti-HBc are not excluded, as this indicates immunity due to hepatitis B vaccination.
- Hepatitis C antibody positive.
- Any other abnormal hematology, biochemistry, or viral serology deemed by an investigator to be clinically significantly abnormal. Abnormal chemistry and/or hematology may be repeated during Screening.
- Chest X-ray (CXR; posterior-anterior) at Screening, or in the 12 months prior to Screening with clinically significant abnormalities not attributable to COPD. If a CXR within the past 12 months is not available but a computerized tomography (CT) scan within the same time period is available, the CT scan may be reviewed in place of a CXR. For subjects in Germany, if a CXR or CT scan is not available in the 12 months prior to Screening, the subject is not eligible for the study.
Electrocardiogram (ECG) finding that is significantly abnormal on the 12-lead ECG obtained at Screening.
- Use of an experimental drug within 30 days or 5 half-lives of Screening, whichever is longer, and/or participation in a study treatment-free follow-up phase of a clinical study within 30 days prior to Screening.
- Use of an experimental medical device or participation in a follow-up phase of an experimental medical device clinical study within 30 days prior to Screening.
- Intolerance or hypersensitivity to albuterol/salbutamol or ensifentrine (RPL554) or any of its excipients/components.
- Prior receipt of blinded study medication in an ensifentrine (RPL554) study.
- Affiliation with the investigator site, including an Investigator, Sub-Investigator, study coordinator, study nurse, other employee of participating investigator or study site or a family member of the aforementioned.
- Inability to read, understand, and/or complete questionnaires (in the opinion of the Investigator).
- A disclosed history or one known to the Investigator of significant non-compliance in previous investigational studies or with prescribed medications.
- Any other reason that the Investigator considers makes the patient unsuitable to participate.
Exclusion Criteria at Randomization (RPL554-CO-301)
- COPD exacerbation or lower respiratory tract infection between Screening and Randomization (defined as use of any additional treatment other than current treatment and rescue medication and/or emergency department or hospital visit). Patients with a severe COPD exacerbation that requires hospitalization may not be rescreened.
- Positive COVID-19 result at Screening or between Screening and Randomization.
- Prohibited medication use between Screening Visit 0 and Visit 1.
Significantly abnormal ECG finding on the 12-lead ECG obtained at Screening as assessed by the investigator or site medical doctor/medically qualified person or on the pre-dose (prior to randomization) ECG obtained at Visit 1.
In the event that the central ECG reviewer discovers a significant ECG abnormality on the Visit 1 ECG, the patient will be discontinued.
- Did not meet one or more of the Inclusion Criteria or met one or more of the Exclusion Criteria.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04535986
|Responsible Party:||Verona Pharma plc|
|Other Study ID Numbers:||
|First Posted:||September 2, 2020 Key Record Dates|
|Last Update Posted:||December 6, 2022|
|Last Verified:||December 2022|
|Studies a U.S. FDA-regulated Drug Product:||Yes|
|Studies a U.S. FDA-regulated Device Product:||No|
Lung Diseases, Obstructive
Pulmonary Disease, Chronic Obstructive
Respiratory Tract Diseases